Recruitment of patients began in March 2005 and data collection was completed in January 2010.[2] The study protocol was published in BMC Neurology in 2007.[1] The main study outcomes were published in The Lancet in 2011[2] and the experimenters continue to publish papers on the trial.[10]

641 patients were randomised into four groups in the study.[2] All received specialist medical care (SMC), which consisted of medication for symptoms such as insomnia and pain, and general advice to avoid extremes of rest and inactivity.[12] One group received SMC alone. Patients in another group additionally received adaptive pacing therapy (APT), and were advised to stay within the limits of activity imposed by the disease to give their bodies the best chance of recovery.[13] The other two groups were both told that they were not ill but deconditioned, and that if they gradually increased their activity, there was nothing to prevent their recovery.[14][15] The cognitive behavioural therapy (CBT) group focused on addressing their presumed fear of activity while the graded exercise (GET) group focused on increasing their activity in a structured manner, with regular aerobic exercise as the eventual goal.

Patients in the APT, CBT and GET groups were offered up to 14 sessions with a therapist over a six-month period, to support them in following their therapy programmes, with a top-up session at 36 weeks. They also received a lengthy manual[13][14][15] explaining their therapy. All participants were offered at least three sessions of SMC.

Patients were assessed at baseline, 12 weeks, 24 weeks and 52 weeks. The main outcome measures were self-rated fatigue and physical function. Secondary measures included the study's objective variables such as a six-minute walking test, a fitness test and economic measures including the number of days of work lost due to fatigue, and the receipt of sickness benefits.[1]

Patients were also followed up (using subjective ratings only) at least two years after randomisation.[4]

The trial's results showed that patients in the CBT and GET groups improved more in self-rated fatigue and physical function than the APT or SMC-only groups.[2] Apart from the GET group improving slightly more than the others on the six-minute walking test,[2] all of the study's objective measures[16][17] and the long-term follow-up data[4] (self-ratings of fatigue and physical function) showed no difference between groups.

The authors reported, in a 2013 paper specifically about recovery, that 22% of patients in the CBT and GET groups had recovered following these therapies, compared to 8% in the APT group and 7% in the SMC-only group.

The PACE trial and other studies that use the Oxford criteria for diagnosis of ME/CFS have had major international impact on popular perceptions of the disease and also on public policies toward treating and researching it.

On February 27, 2011, when the first PACE trial paper was published, researchers Michael Sharpe and Trudie Chalder held a press conference[18][19][20] to discuss their findings. Chalder stated, “twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal.”[21] That assertion has been criticized for grossly overstating the study's actual findings.[22][23][24]

The claims made about the study were covered in the UK and international press.[25][26][27][28][29][30][31] For example, The Daily Mail stated, "Fatigued patients who go out and exercise have best hope of recovery",[32] while The New York Times declared "Psychotherapy Eases Chronic Fatigue Syndrome".[33] According to the British Medical Journal's report on the trial, some participants were "cured."[22]

Many other PACE papers followed, although with relatively little media attention until October 2015, when long-term follow-up results were published in The Lancet Psychiatry.[4][34][35][36][37] The Daily Telegraph ran a front-page story with the headline, "Exercise and positivity can overcome ME."[38][39] The piece stated, "Chronic Fatigue Syndrome is not actually a chronic illness and sufferers can overcome symptoms by increasing exercise and thinking positively, Oxford University has found". The article quoted Professor Sharpe describing ME as a “self-fulfilling prophesy” that happens when patients live within their limits. The article was altered following public pressure but no formal retraction was made. Science also published an article in October 2015 along with comments from Sharpe about the growing criticism outwith the patient community from the broader science community.[40]

In the UK the Science Media Centre is a government-funded body that describes its purpose as being to improve science journalism. Its reporting on ME/CFS has been criticized for bias towards a psychological etiology for the disease.[41]

The sheer size of the PACE trial means that it dominates the evidence base in ME/CFS. Together with other studies of CBT and GET, it is highly influential in UK clinical policy and that of many other countries, both in terms of healthcare provided by government[7] and by private medical insurance.[8]

In the UK, the NICE guidelines for NHS-provided care[7] recommend CBT and GET for ME/CFS. They were published in 2007, before the PACE trial was conducted, but the evidence was based on a few small trials and was considered "somewhat limited".[42] The ME Association has asked for the guidelines to be updated to take into account new treatment evidence, noting, "we assume that the guideline surveillance review that took place in March 2011, and which followed publication of the PACE trial in February 2011, simply ‘rubber stamped’ the 2007 NICE guideline recommendations on the basis that the PACE trial had supported the recommendations relating to CBT and GET."[43] NICE responded, "we still do not feel that the evidence base is substantially evolving in this area at this time" and the guidelines currently remain on the "static" list.[44]

In the US, the Mayo Clinic, Cleveland Clinic, Kaiser Permanente, and numerous key secondary medical education providers, such as UpToDate and WebMD, recommend CBT and GET, using PACE as a reference. CBT and GET are included in the Center for Disease Control's clinical guidelines for CFS, based on the PACE trial evidence.[45]

The PACE trial used the Oxford criteria for diagnosis. Many patients and specialist clinicians consider them overly broad,[46][47] and the National Institutes of Health 2015 P2P report[48] on ME/CFS recommended that the Oxford definition be retired for this reason.

The authors abandoned their protocol-specified main outcome and recovery analyses partway through the trial and replaced them with others.[2][3] They have defended the changes, noting, "All these changes were made before any outcome data were analyzed (i.e. they were pre-specified), and were all approved by the independent Trial Steering Committee and Data Monitoring and Ethics committee."[49] However, 42 scientists, in an open letter to The Lancet, stated that the changes were of "of particular concern in an unblinded trial like PACE, in which outcome trends are often apparent long before outcome data are seen. The investigators provided no sensitivity analyses to assess the impact of the changes and have refused requests to provide the results per the methods outlined in their protocol."[50]

Most notably, the authors introduced post-hoc "normal ranges" for fatigue and physical function.[2] These ranges have been heavily criticised for having thresholds so low that patients could worsen from trial entry and yet be within these normal ranges. The "normal range" for physical function (measured on the SF-36 100-point scale) was 60 and above, even though patients had to score 65 or lower to enter the trial. A score of 60 is close to the mean physical function score (57) of patients with Class II coronary heart failure.[51]

"The average age of participants in the PACE trial is about 39 years old; normative data suggest that people in this age group should have SF-36 scores of about 93. Yet the new 2013 “normal” is a score of 60."[52]

The PACE authors used the "normal ranges", in conjunction with other thresholds, to define clinical effectiveness in the Lancet[53] paper and recovery rates in a later paper in Psychological Medicine.[54]

All Freedom of Information requests to the authors for the main outcome and recovery results according to the protocol-specified analyses, or for the underlying data so that others could conduct the analyses, have been refused.[55][56][57][58]

The study has been criticised for having subjective primary analyses in an unblinded trial.[59] Subjective measures are known to be susceptible to bias, as can arise from expectations and social pressure. The CBT and GET groups, but not the others, were told that there was nothing to stop them from recovering if they gradually increased their activity, and critics have argued that these differential expectations could have inflated their self-assessments.[6][60]

The forty-two scientists and clinicians who wrote an open letter to the Lancet complaining about the PACE trial criticized the study authors' failure to disclose a potential conflict of interest to trial participants.[50] They wrote:

"The investigators violated their promise in the PACE protocol to adhere to the Declaration of Helsinki, which mandates that prospective participants be 'adequately informed' about researchers’ “possible conflicts of interest.” The main investigators have had financial and consulting relationships with disability insurance companies, advising them that rehabilitative therapies like those tested in PACE could help ME/CFS claimants get off benefits and back to work. They disclosed these insurance industry links in The Lancet but did not inform trial participants, contrary to their protocol commitment. This serious ethical breach raises concerns about whether the consent obtained from the 641 trial participants is legitimate."

The investigators published newsletters for participants[61][62][63][64] while the trial was still underway. Critics have said that the material in the third newsletter[63] could have influenced patients' self-reported outcomes. It included a number of positive testimonials from patients in the trial, but without naming their therapies. The PACE authors have argued that this meant that there would be no bias in favour of CBT and GET[49] but Professor James Coyne has dismissed the idea that bias would be expected to affect all four groups equally.[65][66]

The newsletter did, however, announce that the new NICE guidelines, "based on the best available evidence... recommended therapies [that] include Cognitive Behavioural Therapy, Graded Exercise Therapy and Activity Management." There was no explanation of what "Activity Management" was: no group had that title in the PACE trial. Dr. Bruce Levin, a professor of biostatistics at Columbia University and an expert in clinical trial design, said, “To let participants know that interventions have been selected by a government committee ‘based on the best available evidence’ strikes me as the height of clinical trial amateurism”.[22]
The newsletter also contained a less than positive assessment of research on the possibility of an infectious component of ME/CFS, including research by Jose Montoya on herpesviruses and by John Chia on enteroviruses. The newsletter said of Dr Chia's work, for example, "The laboratory work looked convincing, but many patients had significant gastro-intestinal symptoms and even signs, casting some doubt on the diagnoses of CFS being the correct or sole diagnosis in these patients." It is possible that this negative view of evidence of an ongoing infection would have made the rationale for APT appear less plausible and that for CBT and GET more plausible, thus biasing the participants.

An account of another study, in contrast, gave a positive assessment of CBT, saying "cognitive behaviour therapy was associated with an increase in grey matter of the brain and this increase was associated with improved cognitive function".

A survey[67] conducted by the ME Association in 2012 showed that 74% of patients had their symptoms worsen after a course of GET. In contrast, the PACE trial found no apparently meaningful difference in rates of adverse events between the four trial groups,[68] suggesting that APT, CBT and GET added no risk to SMC alone (since all four groups received SMC). However, critics have questioned whether patients actually increased their activity sufficiently in the CBT and GET groups to trigger many serious adverse events:[69][70] the lack of improvement in the step-fitness test in all groups indicates that this is distinctly possible.[17]

The trial investigators have replied to criticism of the trial on a number of occasions, in response to letters to The Lancet concerning their main analyses,[71] Psychological Medicine concerning their recovery analyses,[72] and Lancet Psychiatry concerning their secondary mediation analyses [73] and long-term follow-up paper.[74] A letter to the BMJ by Tom Kindlon[75] drew a reply from the authors[76] that in turn received 31 responses of its own.[77]

The investigators have also responded to a 14,000-word critique by public health expert and journalist Dr David Tuller.[49] Dr Tuller wrote a rebuttal to their response.[78] He has said, “The PACE authors have long demonstrated great facility in evading questions they don’t want to answer”.

Professor James Coyne reported that he agreed to debate the authors on health website National Elf about the trial but that they declined.[79] Professor Simon Wessely was given the vacated National Elf spot and wrote a lengthy article praising the trial, noting that he once described it as "a thing of beauty" and saying, "We can accept that PACE was a good trial and we can have some confidence in its findings".[11]

The PACE Trial has been heavily criticised by patient groups and some researchers and science journalists for a number of methodological problems since its publication. [22][23][24][49][78][80][81][82][83]

Prof Malcolm Hooper and Margaret Williams have followed the PACE trial from its inception in 2004 and provided salutary warnings about the possible issues and problems with the conduct of the trial due to their previous knowledge of the principal investigators research[84][85].

They then published a 400 page critique of the PACE trial in February 2010 'Magical Medicine: How to make a disease disappear' [86]. In February 2011 upon publication of the PACE trial findings, Prof Hooper submitted a comprehensive complaint to the editor of the Lancet and a further detailed response [87][88].

Prof Hooper et al in 2011 published further concerns about the PACE trial and have also examined the role of the Science Media Centre and the insurance industry with the PACE trial [89][90]. Prof Hooper has published a summary of the key dates and chronology of the trial since 2004 [91].

Major Investigation by Investigative journalist and academic in public health & journalism - Dr David Tuller[edit]

Renewed interest in the trial came in October 2015 with public health expert and investigative journalist Dr David Tuller's investigative Tour de Force "Trial by Error: The Troubling Case of the PACE Chronic Fatigue Syndrome Study" publication on Virology Blog which gave a detailed analysis of PACE's methodological problems. Dr Tuller continues to publish articles criticising different aspects of the trial.[94] The main articles for the Trial by Error Series are listed below.

The PACE trial authors with the exception of their response to Virology on October 30 2015 have refused to respond to or engage with David Tuller about any of these concerns. They refused to respond and ignored a number of requests for comments by David Tuller in 2015 and 2016. Similarly Richard Horton, editor of the Lancet has refused to respond to Tuller about these concerns or about retraction of the PACE trial publication. Sir Simon Wessely on behalf of the PACE trial principal investigators did publish an article in November 2015 The PACE trial for chronic fatigue syndrome: choppy seas but a prosperous voyage referring to the growing concerns over the PACE trial. This was published in a blog website called National Elf Service run by the Mental Elf in which he used an analogy of the clinical trial as an ocean liner crossing the Atlantic.[95]

Dr James Coyne, Professor of Health Psychology, at the University Medical Centre Gronigen (UMCG), published on PLoS One Blog on 29 October 2015 'Uninterpretable: Fatal flaws in PACE Chronic Fatigue Syndrome follow-up study'[96]. He gave a talk at Edinburgh University in November 2015 heavily criticising the PACE trial [97][98][99][100]. He spoke again about the PACE study in Belfast in February 2016 where he described it as "a wasteful trainwreck of a study".[101][102] Professor Coyne has also questioned whether the PACE trial paper could ever have been properly peer-reviewed, given the large number of study authors and the small world of British science.[103] He has continued to critique the PACE trial [104].

A former editor of the Lancet analysed the PACE trial and provider her comments on the controversy and concluded "Psychiatrists need to understand that their presence anywhere near this condition is now toxic, and maybe they need to take a step back"[109] .

Prof Jonathan Edwards has declared that "PACE is valueless for one reason: the combination of lack of blinding of treatments and choice of subjective primary endpoint. Neither of these alone need be a fatal design flaw but the combination is". He also stated "the authors have not been meticulous in trying to avoid bias that might arise. On the contrary they appear to have acted in ways more or less guaranteed to maximise bias." [60].

In early 2016, Leonid Schneider, a science journalist, entered the debate and criticised the lack of data sharing by the PACE trial authors and the Lancet and its editor Richard Horton's role in the scandal and compared it to other recent Lancet scandals. [111][112][113].

Prof Andrew Gelman, Professor of Statistics and Political Science at Columbia University, examined the Lancets role in how the PACE trial got taken so seriously and stayed afloat for so long [114][115].

Prof Sten Helmfrid published in the journal Socialmedicinsk tidskrift in September 2016 'Studies on Cognitive Behavioral Therapy and Graded Exercise Therapy for ME/CFS are misleading' that not only the PACE trial but all other studies on CBT/GET by the PACE authors. such that "The underlying model has no theoretical foundation and is at odds with physiological findings. Surveys suggest that the efficacy of CBT is no better than placebo and that GET is harmful. Therefore, cognitive behavioral therapy and graded exercise therapy for ME/CFS are not evidence based."[116]

Sonia Lee, a clinical epidemiologist, published 30 slides critically appraising the PACE trial in February 2017 and gave a damning conclusion that the PACE trial authors should "rectify or retract". [117][118]

Professor Leonard Jason in the Journal of Health Psychology wrote in February 2017 The PACE trial missteps on pacing and patient selection which criticised the issue of patient selection in the trial with the use of the Oxford criteria included those without the disease and the PACE trial investigators did not design and implement a valid pacing intervention in the trial.

Richard Horton, the editor of the Lancet, requested it to be submitted as an official letter but after 6 months of chasing he rejected it and refused to publish the letter [119][120].

On 13 March 2017 David Tuller and the original signatories to the open letter to the Lancet in 2016 and an additional 37 signatories signed an open letter to the Journal of Psychological Medicine. In total 102 signatories signed this open letter regarding the recovery paper of 2013 to the Journal of Psychological Medicine.

On 23 March 2017 David Tuller reported that one of the editors of the Journal of Psychological, Sir Robin Murray, responded with "an unacceptable response." Tuller restated that "That the editors of Psychological Medicine do not grasp that it is impossible to be “disabled” and “recovered” simultaneously on an outcome measure is astonishing and deeply troubling." The open letter was reposted with 17 additional individuals and 23 more charities.

On October 28, 2015, MEAction launched a petition addressed to The Lancet, Psychological Medicine and the PACE trial authors, calling for an independent analysis of the data and the retraction of some of the PACE trial's "misleading claims" based on "absurd 'normal ranges' for fatigue and physical function". The petition was closed in February 2016, having gathered 11,897 signatures from people in sixty-four countries.[5][121]

During International ME Awareness day (12 May) in 2017 due to the intransigence of the PACE researchers for years, a Millions Missing protest in London resulted in hundreds of patients protesting against the PACE trial [123][124][125]

However, the PACE authors and their supporters have been accused of blurring the line between harassment and legitimate criticism of the study. Documentation obtained under the Freedom of Information Act from meetings in 2013 that were attended by some of PACE’s principal investigators include a statement that “harassment is most damaging in the form of vexatious FOIs [Freedom of Information requests].”[137] This framing of FOIA requests as harassment is widely taken to be a reference to the PACE authors, who have complained about the number of FOI requests that they have received for data[138] and who have dismissed several as "vexatious":[139][140][141] the Information Commissioner's Office was told that Professor Peter White “believes that the requests are clearly part of a campaign to discredit the trial” and that “the effect of these requests has been that the team involved in the PACE trial, and in particular the professor involved, now feel harassed and believe that the requests are vexatious in nature.”[138]

The criticisms of the trial's methodology and analyses by patients and others has been referred to by the investigators - and The Lancet - as part of a campaign to undermine the the study. In an editorial comment that accompanied letters criticising the trial, The Lancet described the trial as “rigorously conducted” and questioned whether the “coordination of the response... has been born... from an active campaign to discredit the research”.[142] In an interview on Australian national radio shortly after publication, Dr Richard Horton, The Lancet’s editor, described patients who criticised the trial as “a fairly small, but highly organised, very vocal and very damaging group of individuals”.[143]

But some accuse the investigators of a campaign against patients, labelling them as harassers to undermine their criticisms of the trial, including Angela Kennedy.[144]

The PACE trial authors refused to provide anonymised data to many individuals and also refused to accept the Information Commissioners Office decision for QMUL to release the data in 2015 (see Release of Data/Information Tribunal below). During the PACE trial authors appeal to the Tribunal an article was published during this period by their associates in Nature in which they bizarrely in projection described disabled ME sufferers as “hard-line opponents” of research into chronic fatigue syndrome and compared them with industry lobbyists such as tobacco and climate change denialists. [145]. [146] . Public health expert and journalist David Tuller, who has said, “Wrapping themselves in victimhood, the [PACE authors] have even managed to extend their definition of harassment to include any questioning of their science and the filing of requests for data — a tactic that has shielded their work from legitimate and much-needed scrutiny.” [147][148]

The Science Media Centre (SMC) was found to have orchestrated and publicised the false narrative in 2011 in the UK media about extremists harassing researchers. [149][150]

An article in the Establishment in May 2016, The Hidden Battle For The Rights Of Chronic Fatigue Syndrome Sufferers summarised the campaign to smear ME sufferers and how these psychiatrists after categorising ME as a psychological over two decades then were able to use institutional gaslighting when patients were question the scientific validity of the trial and to stop access to data requests from the PACE trial by framing them as harassment and abuse.

No evidence of anyone with ME/CFS being charged by the police with harassment and death threats has come to light.

The Centre for Welfare Reform published a 64 page report in April 2016 examining the PACE trial and relating the study to the biopsychosocial model and its links and influence from the insurance industry and government welfare reforms. The report titled 'In the Expectation of Recovery' by George Faulkner heavily criticised the PACE trial and stated “The way in which the biopsychosocial model has been used and promoted, without good supporting evidence for many of the claims being made, is unethical.” and “Had homeopaths or a pharmaceutical company conducted a trial and presented results in the manner of the PACE trial the British research community would have been unlikely to overlook its problems.”[154] Dr Simon Duffy writing in the Huffington Post questioned the motive of the research in The Misleading Research at the Heart of Disability Cuts.

The PACE Trial has been the subject of a number of parliamentary enquiries by parliamentarians mainly the Countess of Mar. The Countess of Mar asked questions of the government via a short debate in the House of Lords on the assessment of the PACE trial on 6 February 2013. [156][157] During the court case below in 2015 by Matthees and the Information Commissioners Office v QMUL it was stated by Peter White that he regarded parliamentary debates as harassment and had to brief those taking part in the debate. In November 2016 Kelvin Hopkins MP asked seven written questions relating to the PACE Trial including "request that the Medical Research Council conducts an inquiry into the management of the PACE trial to ascertain whether any fraudulent activity has occurred." and "prevent the PACE trial researchers from being given further public research funding until an inquiry into possible fraudulent activity into the PACE trial has been conducted."

The study authors have been criticised for failing to follow the requirements of the Medical Research Council (who provided significant funding for the trial) to release anonymised trial data.[158]

The 2012 PACE cost-effectiveness paper[16] was published in the journal PLoS One. That journal requires authors, as a condition of submitting their papers, to agree to release the anonymized trial data underlying the paper's analyses upon request. In November 2015 Professor James Coyne made a request to the PACE authors on that basis, but the authors treated his request as a Freedom of Information request and refused it.[159][160] However in March 2016 the PLoS One journal confirmed they had requested the investigators to release the trial data, as they committed to do prior to publication.[161][162]

In 2015 Peter White lobbied the UK government to restrict the Freedom of Information Act 2000 for universities especially for controversial research and cited the PACE trial and compared ME patients requesting data with "climate change science, and research into the health effects of tobacco" [163]

The PACE trial investigators have been asked for 160 pieces of separate information in 35 Freedom of Information requests since 2011.[138] They have dismissed at least three of these claims as "vexatious".[139][140][141][58][164]

A ruling by a UK government body, the Information Commissioner's Office (ICO), on 27 October 2015 ordered Queen Mary University of London (QMUL, the institutional base of the PACE trial's lead investigator Peter White) to release the trial data to a patient who had requested it, subject to appeal within 28 days.[165] Three Freedom of Information requests from 2012 and 2013 were included in the ICO's decision.[166][167][55] An appeal by QMUL was heard by the First-Tier Tribunal on 20-22 April 2016. QMUL responded to a freedom of information request confirming the cost of its legal fees for the tribunal totalled £245,745.27 (around USD350,000).[168][169][170] The First-Tier Tribunal judgement was published on 16 August 2016, roundly dismissing the appeal by QMUL, and deciding that the PACE trial data should be released.[171][172] The university has not yet stated whether it will appeal the judgement.[173]

The PACE patient consent form was released through a Freedom of Information request.[174]

Dr Richard Horton, editor of The Lancet, stated on 18 April 2011 in a national Australian radio interview: "The Freedom of Information requests and the legal fees that have been racked up over the years because of these vexatious claims has added another £750,000 of taxpayers’ money to the conduct of this study".[175]

Professor Coyne's own request for the data was dismissed under the Freedom of Information Act by the study authors as "vexatious" and as having an "improper motive".[139]

Scientists Ronald Davis, David Tuller, Bruce Levin, and Vincent Racaniello requested the PACE trial data in December 2015.[185] Their request was rejected by the trial investigators.[186]. On International ME Awareness day in May 2016 in an interview with an advocate's article called PACE-Gate, Dr Racaniello stated "“I think they are going to ignore, obfuscate, and give their usual responses until we are all dead. I don’t have hope that the PACE authors, or Lancet, will respond in any meaningful way until there is more of an outcry.” [187].

A number of patient charity groups and individuals have called for the release of the PACE data, including some outside the ME/CFS community who advocate "open data" in science. These calls include:

2016: open letters from two patient charities, in Australia, ME/CFS Australia (SA) Inc and Emerge Australia, calling for the data to be released.[188][189]

2016: an open letter the European ME Alliance (EMEA) representing patient group charities from 12 European countries (Belgium, Denmark, Finland, Germany, Holland, Iceland, Ireland, Norway, Spain, Sweden, Switzerland and UK), calling for the data to be released.[190]

2016: an open letter by Mark Berry of Phoenix Rising, a US based non profit with the largest ME patient forum membership in the world, calling for the data to be released.[191]

2015: a blog post by Dr Richard Smith, former editor of The BMJ, who said that the PACE authors' institutions were "making a mistake... the inevitable conclusion is that they have something to hide.”[206] and in article for F1000 Research [207]

A total of 29 patient charity groups from 15 countries wrote in support of releasing the anonymized PACE trial data. [209][210]

A ME charity polled on the question "Should or should not the anonymised data from the PACE trial be released for independent analysis?" As at 17 March 2016, 1391 voters took part and 99% (1378 voters) voted for 'Should be released'. 0% (5 voters) voted for 'Should not be released' [211].

Both cofounders of Retraction Watch, Ivan Oransky and Adam Marcus, added their weight behind patients in the refusal of the PACE trial investigators to release the anonymised data in article in STAT News feature 'The Watchdogs Keeping an eye on misconduct, fraud, and scientific integrity' To keep science honest, study data must be shared and concluded "when researchers refuse to share data, and how they came up with it, they lose the right to call what they do science".[212]

Alem Matthees , an Australian ME sufferer, submitted a FOIA request to the PACE trial authors who were ordered to provide the requested data by the Information Commissioners Office. This decision was appealed by them to the Information Tribunal and was heard on April 20th 2016 at a three day hearing.

The tribunal took evidence under the normal rules of court. The tribunal also concluded of the expert witness for the PACE authors that "It was clear that his assessment of activist behaviour was, in our view, grossly exaggerated and the only actual evidence was that an individual at a seminar had heckled Professor Chalder” and "clearly in our view had some self-interest, exaggerated his evidence and did not seem to us to be entirely impartial. What we got from him was a considerable amount of supposition and speculation, with no actual evidence to support his assertions or counter the respondents arguments." The tribunal panel noted that the Commissioner had referred to Professor Anderson’s “wild speculations” that “young men, borderline sociopathic or psychopathic” would attempt to identify trial participants from the anonymised data, and said that his views “do him no credit”. [217]

The decision noted in the evidence that "Contrast instead Professor Chalder when she accepts that unpleasant things have been said to and about PACE researchers only, but that no threats have been made either to researchers or participants. The highest she could put it was some participants stated that they had been made to feel "uncomfortable" as a result of their contact with and treatment from her, not because of their participation in the trial per se. There is no evidence either of a campaign to identify participants nor even of a risk of an 'insider threat'.”

Moreover, regarding the independent Cochrane review it was admitted in the tribunal that "Professor Chalder states that disclosure to the Cochrane review does not count as disclosure to independent scientists as all three of the PACE principal investigators sat on the review panel."

Additionally, a UK ME sufferer submitted a FOI request in June 2016 and established that the PACE trial investigator's university paid £245,745.27 for legal fees to defend their case in the tribunal against the original ICO decision. [218][219]

Virology blog published the re-analysis on 21 September No ‘Recovery’ in PACE Trial, New Analysis Finds and concluded " The results should put to rest once and for all any question about whether the PACE trial’s enormous mid-trial changes in assessment methods allowed the investigators to report better results than they otherwise would have had. While the answer was obvious from Dr. Tuller’s reporting, the new analysis makes the argument incontrovertible."

'A Rejoinder to Sharpe, Chalder, Johnson, Goldsmith and White' was published by Dr Carolyn Wilshire, Tom Kindlon and Simon McGrath in response to the PACE authors reply to their original publication [227]. Wilshire et al disproved again the PACE trials misleading claims as recovery was a strong claim and did not adhere to the core meaning of the word, no evidence that the original protocol specified definition was too stringent and absolute recovery rates from other studies were not legitimate source of support for the recovery definition used. It reinforced the original conclusion that "The PACE trial provides no evidence that CBT and GET can lead to recovery from CFS. The recovery claims made in the PACE trial are therefore misleading for patients and clinicians".

Instead of engaging with critics by releasing other additional requests for data, the PACE trial authors updated their guidelines in January 2017 for those requesting access to the PACE trial data which further restricted access by requiring "formal agreement" with "precise analytic plans, and plans for outputs" [228]. Prof James Coyne commented that it is "a ruse to trap the unwary in endless haggling and appeal, while protecting the PACE investigators from the independent reanalysis of the claims, which they have already declared poses a reputational risk to them". [229]

Prof Coyne explained in his blog of the 'Last ditch attempt to block publication of special issue of Journal of Health Psychology foiled' and that anonymous and powerful PACE proponents made threats to the publisher of JHP, SAGE Publications, that made them reluctant to publish the special edition. He explained in his blog "Some threats were made to Sage Publications, the publisher of Journal of Health Psychology, which expressed a reluctance to go forward as planned. As often happens with these kind of pressures, we weren’t told the identity of the complainant. It was clear that whoever s/he was, this person was powerful in being able to grind to a halt of making the special issue available, complete with the introductory editorial that was not previously available.'"

It transpired that "When the effort to block publication of the special issue failed, the PACE investigators got criticism posted at Science Media Centre." [249].

The Science Media Centre put out its own "expert reaction" press release to UK journalists minutes before the special edition was available to spin the story about the PACE scandal and distract and refocus away from the central problems with the scandal [250]. The Science Media Centre ignored the glaring problems and instead made personal attacks agains the authors.

Prof James Coyne had requested anonymised data in 2015 from the PACE trial authors from the Cost Effectiveness paper. He pursued this request throughout 2015 and 2016 but was also refused as "vexatious". After 18 months, PLOS issued an Expression of Concern on May 2nd 2017. It stated "We conclude that the lack of resolution towards release of the dataset is not in line with the journal’s editorial policy and we are thus issuing this Expression of Concern to alert readers about the concerns raised about this article [255]. The Editors of PLOS One, Iratxe Puebla and Joerg Heber, wrote in PLOS One Blog "Since we feel we have exhausted the options to make the data available responsibly, and considering the questions that were raised about the validity of the article’s conclusions, we have decided to post an Expression of Concern to alert readers that the data are not available in line with the journal’s editorial policy" [256]. Retraction Watch reported on the development [257]

David Tuller reported in July 2017 Trial By Error: The CDC Drops CBT/GET the CDC updated their treatment recommendations and "the agency has “disappeared” all mention of CBT and GET as treatment or management strategies." It was reported by Tuller that the key members of the PACE trial had a long history with the CDC and "For advocates, the CDC’s removal of the CBT/GET recommendations represents a major victory. “I think it’s huge,” said Mary Dimmock, an advocate who has long pressured the CDC to revise its website." The removal of CBT and GET has been "heralded as an important" by patient charities [258]. David Tuller in Undark reported on this development as CDC Removes Reference to Disputed ME/CFS Therapies From Website. [259].

Trevor Butterworth is the Editor of 'Sense About Statistics,' an online collaboration between the American Statistical Association and Sense About Science USA.[262]

"...the way PACE was designed and redesigned means it cannot provide reliable answers to the questions it asked. There is really not a lot that can be said to mitigate that; it’s a terminal prognosis."

Professor Coyne is Professor of Health Psychology, University Medical Center, Groningen and University of the Netherlands; Distinguished Visiting Professor at the Institute for Health Policy, Rutgers, the State University of New Jersey; and Professor Emeritus of Psychology in the Department of Psychiatry, University of Pennsylvania. He is one of the most cited psychologists in the academic literature.

"The data presented are uninterpretable. We can temporarily suspend critical thinking and some basic rules for conducting randomized trials (RCTs), follow-up studies, and analyzing the subsequent data. Even if we do, we should reject some of the interpretations offered by the PACE investigators as unfairly spun to fit what [is] already a distorted positive interpretation of the results."[65]

"The self-report measures do not necessarily capture subjective experience, only forced choice responses to a limited set of statements."[65]

"One of the two outcome measures, the physical health scale of the SF-36 requires forced choice responses to a limited set of statements selected for general utility across all mental and physical conditions."[65]

"The validity [of the] other primary outcome measure, the Chalder Fatigue Scale depends heavily on research conducted by this investigator group and has inadequate validation of its sensitivity to change in objective measures of functioning."[65]

Professor Coyne gave a public talk criticising the PACE trial in Edinburgh in November 2015. Video footage is available[97][98][99], as are a slide show[100], a full[263] and an edited transcript[264][265] and an audio recording.[266]

He spoke again about the PACE study in Belfast in February 2016 where he described it as "a wasteful trainwreck of a study".[101][102]

Professor Coyne has questioned whether the PACE trial paper could ever have been properly peer-reviewed, given the large number of study authors and the small world of British science.[103]

Professor Coyne and Professor Laws of the University of Hertfordshire have criticised, in a joint letter to Lancet Psychiatry, the long-term follow-up analysis of the PACE trial that was published in 2015.[107] Referring to the results of the study as a whole, they said:

"There are no group differences, and the overall mean short-form 36 (SF-63) physical functioning score is less than 60. It is useful to put this number in context. 77% of the PACE trial participants were women, and the mean age of the trial population was 38 years, with no other disabling medical conditions. Patients with lupus have a mean physical functioning score of 63, patients with class II congestive heart failure have a mean score lower than 60, and normal controls with no long-term health problems have a mean score of 93."

Professor Ronald Davis is a world-famous geneticist at Stanford University, known for work that enabled the Human Genome Project.

“I’m shocked that the Lancet published it... The PACE study has so many flaws and there are so many questions you’d want to ask about it that I don’t understand how it got through any kind of peer review.”[22]

Professor Edwards, of University College London, is internationally known for his pioneering work in establishing B-cell depletion therapy as an effective treatment for rheumatoid arthritis.

“It’s a mass of un-interpretability to me…All the issues with the trial are extremely worrying, making interpretation of the clinical significance of the findings more or less impossible....Within the circle who are involved in this field, it seems there were a group who were prepared to all sing by the hymn sheet and agree that PACE was wonderful. But all the issues with the trial are extremely worrying, making interpretation of the clinical significance of the findings more or less impossible.”[22]

"A treatment like GET is simply not appropriate for a disease like ME which is linked to infection and metabolic abnormalities. Given the close relationship between exertion and symptoms, it follows that asking a patient to increase their activity levels is as logical as advising smokers with lung cancer to gradually increase the number of cigarettes they smoke"[268]

Leonard Jason is a professor of psychology at DePaul University in Chicago, Illinois, and director of its Center for Community Research.

“The PACE authors should have reduced the kind of blatant methodological lapses that can impugn the credibility of the research, such as having overlapping recovery and entry/disability criteria.”[22]

"My key points are that the PACE trial investigators were not successful in designing and implementing a valid pacing intervention and patient selection ambiguity further compromised the study’s outcomes."[269]

Dr Tuller is is academic coordinator of the University of California, Berkeley's joint masters program in public health and journalism. He was a reporter and editor for 10 years at the San Francisco Chronicle, served as health editor at Salon.com and frequently writes about health for The New York Times. He has written extensively about the PACE trial.[94]

"The study included a bizarre paradox: participants’ baseline scores for the two primary outcomes of physical function and fatigue could qualify them simultaneously as disabled enough to get into the trial but already 'recovered' on those indicators–even before any treatment. In fact, 13 percent of the study sample was already 'recovered' on one of these two measures at the start of the study."[22]

"In the middle of the study, the PACE team published a newsletter for participants that included glowing testimonials from earlier trial subjects about how much the 'therapy' and 'treatment' helped them. The newsletter also included an article informing participants that the two interventions pioneered by the investigators and being tested for efficacy in the trial, graded exercise therapy and cognitive behavior therapy, had been recommended as treatments by a U.K. government committee 'based on the best available evidence.' The newsletter article did not mention that a key PACE investigator was also serving on the U.K. government committee that endorsed the PACE therapies."[22]

"The PACE team changed all the methods outlined in its protocol for assessing the primary outcomes of physical function and fatigue, but did not take necessary steps to demonstrate that the revised methods and findings were robust, such as including sensitivity analyses. The researchers also relaxed all four of the criteria outlined in the protocol for defining 'recovery.' They have rejected requests from patients for the findings as originally promised in the protocol as 'vexatious.'"[22]

"The PACE claims of successful treatment and 'recovery' were based solely on subjective outcomes. All the objective measures from the trial—a walking test, a step test, and data on employment and the receipt of financial information—failed to provide any evidence to support such claims. Afterwards, the PACE authors dismissed their own main objective measures as non-objective, irrelevant, or unreliable."[22]

"In seeking informed consent, the PACE authors violated their own protocol, which included an explicit commitment to tell prospective participants about any possible conflicts of interest. The main investigators have had longstanding financial and consulting ties with disability insurance companies, having advised them for years that cognitive behavior therapy and graded exercise therapy could get claimants off benefits and back to work. Yet prospective participants were not told about any insurance industry links and the information was not included on consent forms. The authors did include the information in the 'conflicts of interest' sections of the published papers."[22]

"The Lancet Psychiatry follow-up had null findings: Two years or more after randomization, there were no differences in reported levels of fatigue and physical function between those assigned to any of the groups... Yet the authors, once again, attempted to spin this mess as a success."[271]

"The study’s primary case definition for identifying participants, called the Oxford criteria, was extremely broad; it required only six months of medically unexplained fatigue, with no other symptoms necessary. Indeed, 16% of the participants didn’t even have exercise intolerance—now recognized as the primary symptom of ME/CFS".

"After the trial began, the researchers tightened their definition of harms, just as they had relaxed their methods of assessing improvement."

"[T]he study was unblinded, so both participants and therapists knew the treatment being administered. Many participants were probably aware that the researchers themselves favored graded exercise therapy and another treatment, cognitive behavior therapy, which also involved increasing activity levels. Such information has been shown in other studies to lead to efforts to cooperate, which in this case could lead to lowered reporting of harms."

""The many wrongs committed by psychiatry and medicine to the ME/CFS community can only be righted when the Pace trial is ultimately seen for what it is: a disgraceful confidence trick to reduce patient compensation payments and benfits.”. [273].

Serious risks to clinical patient safety caused by unsound claims made about the efficacy of CBT and GET following the PACE trial;

Gross discrepancies between research and clinical cohorts, and how clinical patients (and the physiological dysfunction associated with them) appear to have been actively excluded from PACE and other research by the research group involved in PACE, which has, ironically, caused serious resulting risks to clinical patient safety in the UK in particular;

Related to the above, gross discrepancies in how various sets of patient criteria were used (and/or rejected), including but not limited to a changing of the London criteria by PACE authors from its original state, a set of criteria which was already controversial and problematic to start with for a number of reasons;

Failure of the PACE trial authors to acknowledge the range and depth of scientific literature documenting serious physiological dysfunction in patients given diagnoses of ME or CFS, and how CBT and GET approaches may endanger patients in this context;

The inclusion of major mental illnesses in the research cohort;

The distortion by PACE trial researchers of 'pacing' from an autonomous flexible management strategy for patients into a therapist led Graded Activity approach;

The post hoc dismissal of adverse outcomes as irrelevant to the trial, in direct contradiction to what is scientifically known about the physiological dysfunctions of people given diagnoses of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome;

The instability of 'specialist medical care' as a treatment category, and the lack of any sound category of 'control' group.

Tom Kindlon has also written a large number of letters and comments that have been published in medical journals in response to the published papers.

Among many other published letters that have been critical of the trial, many are from people who have identified themselves as patients. For example, most of the letters published by The Lancet criticising the 2011 PACE paper were from patients or representatives of patients' groups.[277][278][279]

Dutch patient Frank Twisk of the ME-de-patiënten Foundation has also published criticism of the PACE trial.[281]

"The PACE trial investigated the effects of CBT and GET in chronic fatigue, as defined by the Oxford criteria, not in chronic fatigue syndrome, let alone myalgic encephalomyelitis".

"[T]he positive effect of CBT and GET in subjective measures, fatigue and physical functioning, cannot be qualified as sufficient. Mean short form-36 physical functioning scores in the CBT group (62·2) and the GET group (59·8) at follow-up were below the inclusion cutoff score for the PACE trial (≤65)3 and far below the objective for recovery as defined in the PACE protocol (≥85)."

"The vast majority of patients improved subjectively by specialist medical care and APT to the same level as by CBT and GET, without any additional therapies, including CBT and GET, or by other therapies."

"[L]ooking at subjective outcomes at follow-up and objective outcomes in earlier studies, such as physical fitness, return to employment, social welfare benefits, and health-care usage, CBT and GET, like specialist medical care and APT, cannot be qualified as effective".

There is a currently published trial register[282] and there is a version of the register that is no longer available on the web but has been archived.[283] Both versions contain slightly different details. The archived version contains the details of the trial's pre-specified endpoint analyses.

The trial's main outcomes, and some selected secondary outcomes, were reported in The Lancet.[2] Forty-four letters were submitted in a response that the journal's editor described as "swift and damning".[142]

ME/CFS patient Graham McPhee and others created a video animation - How's that recovery? - explaining problems with the new analyses that had replaced those specified in the study protocol. Sam Carter applied the new fatigue and physical function recovery criteria to the data from the FINE trial and found that doing so increased the number of "recovered" patients six-fold, compared to the original criteria.[311]

Patient-advocate Peter Kemp also criticized the study, stating that the authors had "twisted the SF-36 Physical Function subscale to suit their needs."[312]

Patients created a tongue-in-cheek song video to satirically criticize the recovery paper results.[313]

The paper states that at least two years after patients were randomised, "there were no significant differences" in outcomes between the treatment groups. This indicated that APT, CBT and GET added nothing to specialist medical care (SMC), which all groups received. However, the study authors interpreted the results as favouring CBT and GET.

This short paper published in Trials Journal concluded: "Approximately half of the effect of each of CBT and GET [...] on physical function was mediated through reducing avoidance of fearful situations".[340]

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